Abstract 5016: Retinoic acid receptor responder 3 expression suppresses colorectal cancer cell growth in vitro and is a stage-independent prognostic marker in colorectal cancer patients in vivo

Abstract

Abstract Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. Whilst adjuvant chemotherapy can improve survival in Dukes’ C patients, its application on Dukes’ B patients is controversial. Identification of factors that can predict recurrence in the latter group may facilitate classification of high risk patients for receiving adjuvant therapy. Retinoic acid receptor responder 3 (Rarres3) was firstly identified as the retinoid induced class II tumor suppressor in human keratinocytes and psoriatic lesions. In breast, head and neck, lung and gastric cancer cell lines, induced expression of Rarres3 by retinoid can inhibit cell proliferation. Less is known of its effect on colon cancer. Using real-time quantitative RT-PCR, coupled with in vitro functional assays, we have characterized the role of Rarres3 in colorectal cancer development. By comparing the mRNA expression level of Rarres3 in 405 CRCs and 19 colon cancer cell lines with 63 paired normal colons, Rarres3 is down-regulated in most of the CRCs and cell lines. Loss of Rarres3 expression is strongly associated with Dukes’ D patients (p=0.009) and well or moderately differentiated tumor type (p=0.016). Kaplan-Meier analysis demonstrated an improved overall survival (p=0.001) for patients with high expression of Rarres3 by log-rank test. Specifically, there is a prolonged overall survival (p=0.007) and disease free (p=0.012) for Dukes’ B patients (n=158). In multivariate Cox Regression analysis, Rarres3 is an independent factor to predict overall survival (HR=0.473, p=0.001) and disease free (HR=0.557, p=0.047) apart from lymphovascular invasion and Dukes’ stages. Rarres3 protein expression can be induced in colon cancer cell lines by treatment with either interferon-γ (IFNγ) or all-trans retinoic acid (ATRA). Stable transfection of Rarres3 into SW480 colon cancer cells led to inactivation of Akt signaling pathway, suppression of cell growth and enhancement of cell apoptosis via capase-1 activated apoptotic pathway in response to 5-fluorouracil treatment. In addition, we found that Rarres3 is a Wnt target in which its expression is suppressed during Wnt activation and vice versa in colon cancer cell lines. In summary, Rarres3 expression can be induced by IFNγ and ATRA, causing suppression of cell growth and sensitization of cancer cells to apoptosis. Loss of Rarres3 expression in CRCs is predictive of tumor recurrence and poor prognosis especially in Dukes’ B patients, thus aids in molecular stratification of high risk patients. The results also raise the possibility for the use of IFNγ and ATRA in CRC treatment especially in the high risk Dukes’ B subgroup. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5016.